JP7353687B2 - Use of ketamine in the treatment of cachexia - Google Patents

Description

CROSS-REFERENCE This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 62/960,255, filed January 13, 2020. The entire disclosure of the above application is incorporated into this application by reference.
Technical field
The present invention relates to the use of ketamine in the treatment of cachexia; in particular, ketamine is used in the treatment of cachexia caused by 5-FU treatment.

5-Fluorouracil (5-FU) has been used in cancer treatment for nearly 50 years and can be used to treat a variety of cancers. Although 5-fluorouracil is effective in treating cancer, it also causes many side effects such as nausea, vomiting, diarrhea, mucosal inflammation, headache, muscle weakness, hair loss, myocardial infarction, or pneumonia. Therefore, taking 5-FU is a great burden for cancer patients.

Cachexia (also known as cachexy) is a complex metabolic syndrome caused by this disease. Poor metabolism and anorexia nervosa often cause patients to feel abnormally weak, and the main symptoms include muscle weakness and weight loss. Other symptoms include decreases in albumin and hemoglobin and increases in inflammatory factors such as interleukin-6 (IL-6) and reactive protein (CRP). The muscle wasting symptoms of cachexia cannot be reversed simply by providing nutrients. Increasing food intake or increasing nutritional intake cannot prevent or stop the patient's continued weight loss.

Current treatments can only alleviate symptoms by treating the disease that causes cachexia (such as cancer), but they are often ineffective and difficult to cure. Exacerbations of cachexia are usually alleviated by muscle activity, the administration of drugs that stimulate appetite or reduce nausea, direct administration of nutritional drugs, or other supportive care. Therefore, there is an urgent need to develop drugs or methods that can effectively ameliorate cachexia syndrome and improve the survival rate of cancer patients.

SUMMARY OF THE INVENTION An embodiment provided herein is a method for the treatment of cachexia, comprising administering a therapeutically effective amount of ketamine to a subject treated with 5-FU.

In certain embodiments, the human dose of ketamine is 1-100 mg/60 kg per week.

In certain embodiments, ketamine is administered parenterally.

In certain embodiments, the treatment ameliorates weight loss due to cachexia.

In certain embodiments, treatment increases survival.

Another embodiment provided herein is a pharmaceutical composition for the treatment of cancer, comprising 5-FU, ketamine, and a pharmaceutically acceptable carrier; wherein a human dose of ketamine is , 1-100mg/60kg per week.

Another embodiment provided herein is a method for the treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 5-FU and ketamine.

In certain embodiments, the human dose of ketamine is 1-100 mg/60 kg per week.

In certain embodiments, the pharmaceutical composition is administered parenterally.

In certain embodiments, ketamine and 5-FU are administered simultaneously or separately.

DESCRIPTION OF THE INVENTION The following embodiments are made to clearly demonstrate the above and other technical contents, features, and advantages of the present disclosure. Through the description by embodiments, those skilled in the art will clearly understand the technical approaches and effects that this disclosure employs to achieve the above-identified aspects.

Unless otherwise defined, all technical and scientific terms used herein have the same definition as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" or "and" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. Section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Unless otherwise specified, all materials used herein are commercially available and readily available.

As used herein, the term "about" refers to ±15% or ±10% deviation from a specified amount in one embodiment; ±5% deviation from a specified amount in a preferred embodiment; It refers to a measured quantity such as a dose that has a deviation of ±1% from a specified quantity; or in the most preferred embodiment a deviation of ±0.1% from a specified quantity; whereas the property of the substance to which the quantity relates is not influenced thereby. do not have.

5-Fluorouracil (herein abbreviated as 5-FU) is a type of pyrimidine analogue and is primarily used in the treatment of tumors. It is currently believed that the mechanism of action of 5-FU is to further inhibit DNA synthesis by inhibiting the function of thymidylate synthase.

Side effects of 5-FU include severe dehydration, bone marrow suppression, enterocolitis, oral ulcers, dermatitis, angina and myocardial infarction, acute renal failure, interstitial pneumonia, liver damage, jaundice, and diarrhea. 5-FU can also cause acute central nervous system damage (leukoencephalopathy) and central nervous system degeneration.

Ketamine (IUPAC: (R,S)-2-(2-chlorophenyl)-2-methylamino-cyclohexan-1-one), also known as Special K, is a noncompetitive NMDA receptor antagonist that was first introduced in 1960. It has been used for anesthesia, analgesia, and sedation since the 1990s. Ketamine is metabolized by cytochrome P450 in the liver and binds to various receptors, including NMDA, producing an anesthetic effect.

Ketamine can inhibit the activation of NMDA receptors induced by glutamine (a neurotransmitter in the central nervous system), inhibiting the release of glutamine from presynaptic neurons and inhibiting the effects of the inhibitory neurotransmitter GABA. It is also possible to increase

As used herein, "ketamine" may refer to racemic or enantiomerically enriched (eg, enantiomerically pure) forms. In one embodiment, the ketamine according to the invention is racemic ketamine. In another embodiment, the ketamine according to the invention is enantiomerically enriched ketamine. In certain embodiments, the ketamine according to the invention is the S enantiomer or the R enantiomer.

As used herein, the dosage of a drug is, for example, the number of grams of drug administered per kilogram of body weight (g/kg) or the number of milligrams of drug administered per kilogram of body weight (mg/kg). It is defined as the weight of drug administered per kilogram of body weight.

The terms "about" or "approximately" as used herein mean an acceptable degree of deviation as understood by those skilled in the art, and may vary to some extent depending on usage in the text. Generally speaking, for example, "about" or "approximately" can mean a value within ±10%, ±5%, or ±3% of the value.

As used herein, the terms "treatment," "improvement," or similar terms refer to the alleviation, alleviation, or amelioration of at least one disease symptom or condition by treatment or prevention, prevention of new symptoms, disease or physiological Including suppressing a condition, preventing or delaying the onset of a disease, causing recovery of a disease or physiological condition, delaying a physiological condition caused by a disease, and cessation of symptoms or physiological conditions of a disease.

The term cachexia (also known as cachexy) as used herein refers to persistent severe weight loss, anorexia, weakness, anemia, and loss of protein, fat, and Symptoms caused by abnormal carbohydrate metabolism. Cachexia is clinically defined as a syndrome whose main symptoms are anorexia, anemia, and weight loss. Cachexia can occur in a variety of conditions, including tumors, chemotherapy, anorexia, severe trauma, gastrointestinal malabsorption, weight loss, anemia, obesity, and severe sepsis, among which tumors Induced cachexia is the most common and is called tumor cachexia.

Pharmaceutical compositions of the invention can be used to treat cachexia in a subject. Specifically, the pharmaceutical compositions of the invention can be administered to a subject at risk of developing cachexia or experiencing symptoms associated with cachexia to prevent the development of cachexia. can be avoided or the progression of cachexia can be ameliorated or delayed.

The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a compound or drug that is capable of alleviating one or more disease symptoms or physiological conditions after ingestion of the drug by a patient. means. As a result, intentional changes in signs, symptoms, or causes or other physiological systems can be reduced and/or alleviated. For example, an "effective amount" for treatment includes a dose of a compound provided by the invention that is capable of significantly alleviating symptoms of disease in clinical practice.

According to the invention, a therapeutically effective amount will vary depending on the severity of the disease, age of the patient, health status of the patient, potential risk of cancer, or other factors.

According to the invention, the compositions and other pharmaceutical ingredients described herein need not be administered as the same pharmaceutical composition, but may be administered in different ways due to their different physical and chemical properties. .

The term "composition" or "pharmaceutical composition" herein refers to a mixture of at least one drug and other carrier. Carriers include, but are not limited to, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, or combinations thereof.

The term "pharmaceutically acceptable" as used herein refers to a reasonably medically acceptable drug that is free from undue toxicity, irritation, allergic reactions, or other problems or complications, and has a fairly reasonable benefit/risk ratio. means a compound, composition, and/or dosage form that, within the scope of reasonable judgment, is suitable for use in contact with the tissues of a user (such as a human). Each carrier is "acceptable" provided that it is compatible with the other formulation ingredients.

The term "carrier" herein refers to a non-toxic compound or drug that has the function of helping cells or tissues absorb the drug.

Examples of suitable excipients include lactose, dextrose, sucrose, sorbose, mannose, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup. and methylcellulose, but are not limited to these.

The compositions may further include lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; sweetening agents; and flavoring agents. good.

According to the present invention, the drugs of the present invention can be administered in a variety of ways, including but not limited to intravenous injection, oral administration, parenteral administration, intraocular administration, intrapulmonary administration, or topical administration, or a combination of these routes of administration. It can be applied to various administration techniques.

According to the invention, the drug of the invention is used for intraperitoneal injection.

According to the invention, the pharmaceutical compositions include troches, pills, powders, lozenges, sachets, tablets, elixirs, suspensions, emulsions, solvents, syrups, soft and hard gelatin capsules, suppositories, sterile injectables and packages. It can be in powder form.

The present invention provides a method for treating cachexia caused by 5-FU, comprising administering to a patient a therapeutically effective amount of ketamine, wherein the patient is receiving 5-FU treatment. .

The present invention also provides the use of ketamine to prepare a medicament for improving cachexia, administered to patients undergoing 5-FU treatment.

In a preferred embodiment, the drug is used to improve weight loss due to cachexia.

In a preferred embodiment, the drug is used to improve survival.

The invention also provides a method of treating cancer comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises 5-FU, ketamine, and a pharmaceutically acceptable containing a carrier.

In preferred embodiments, the cancer includes, but is not limited to, anal cancer, breast cancer, colorectal cancer, oropharyngeal cancer, stomach cancer, pancreatic cancer, skin cancer, or head and neck cancer. .

In a preferred embodiment, ketamine and 5-FU are administered to the patient simultaneously or separately.

The present invention also provides a pharmaceutical composition for treating cancer, comprising 5-FU, ketamine, and a pharmaceutically acceptable carrier.

In a preferred embodiment, the dose of ketamine in the pharmaceutical composition is at least about 60% of the dose of 5-FU.

In a preferred embodiment, the human dose of ketamine is 1-100 mg/60 kg per week.

In a further preferred embodiment, the human dose of ketamine is 1-50 mg/60 kg per week.

In a preferred embodiment, the human dose of ketamine is about 25 mg/60 kg per week.

Capecitabine, an anticancer drug, is absorbed orally and converted to 5-FU in tissues, exerting anticancer effects. Thus, in certain embodiments, 5-FU can be administered to a patient in the form of capecitabine.

Norketamine (IUPAC: (R,S)-2-(2-chlorophenyl)-2-(amine)cyclohexanone) is a metabolite of ketamine after demethylation and has a lower and slower activity than ketamine.

Thus, in certain embodiments, ketamine can be administered to a patient in the form of norketamine. As used herein, "norketamine" may refer to racemic or specular isomer enriched forms (eg, pure enantiomers).

material and method
Mice (obtained from the National Center for Experimental Animals) aged 6 to 12 weeks were individually housed in a thermostatic chamber at a temperature of 24 ± 1°C under a 12-hour light/dark cycle.

Mice were divided into four groups, and each group contained four mice.

5-FU was formulated at a dose of 50 mg per kilogram of mouse (50 mg/kg) and injected intraperitoneally (i.p.) once a day for 3 consecutive days.

Additionally, ketamine was prepared at a dose of 15 mg/kg or 30 mg/kg and injected intraperitoneally (i.p.) into mice 24 h after the last injection of 5-FU.

Physiological saline was used as a carrier for 5-FU and ketamine as in the control group.

After completing the above injection, the survival rate, body weight, and food intake of the mice were observed.

Experimental Results The experimental results of this example are shown in Tables 1-3.

As can be seen from the results, every minute mice were injected with 50 mg/kg 5-FU intraperitoneally, but on day 17 after 5-FU injection, 50 mg/kg 5-FU and 15 mg/kg The survival rate for the group injected with ketamine was only 25%. However, there is still a 100% survival rate in the 50 mg/kg 5-FU and 30 mg/kg ketamine groups.

Next, regarding food intake, the control group consumed 235.2 grams (g) of food (standard deviation: 4.0). The 5-FU injection group ingested 189.6 g of food (standard deviation: 7.5). The two groups given 5-FU and ketamine, respectively, had similar intakes. The 15 mg/kg ketamine group ingested 215.0 g of food (standard deviation: 8.3). The ketamine 30 mg/kg group ingested 219.1 g of food (standard deviation: 5.7).

Furthermore, regarding body weight changes, mice in the group injected with 50 mg/kg of 5-FU and 15 mg/kg of ketamine showed an average weight loss of 19.9%, similar to the group injected with 5-FU alone. In contrast, in the 5-FU 50 mg/kg and ketamine 30 mg/kg group, the weight loss was only 7.5%, close to that of the control group (0.2% decrease).

Table 1: Weight of mice in the final observation carry forward (LOCF) population at the end of the experiment.

Table 2: Weight changes of mice in the LOCF population at the end of the experiment

Table 3: Percent weight change of mice in the LOCF population at the end of the experiment

According to the content disclosed in this application, animal studies have shown that 5-FU injection can cause symptoms and complications of cachexia, such as weight loss, decreased food and water intake, and decreased survival rate. The combination of ketamine and ketamine improves the above symptoms. Therefore, one skilled in the art can know from this specification that ketamine can be used to improve or treat cachexia with 5-FU.

While preferred embodiments of this disclosure are shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only and can be practiced in combination. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be used in implementing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (5)

A pharmaceutical composition for the treatment of cachexia in a subject suffering from cancer induced by a chemotherapeutic agent for the treatment of cancer, comprising a therapeutically effective amount of ketamine, the composition comprising:
A pharmaceutical composition, wherein the dose of ketamine is 1-100mg/60kg per week . 2. The pharmaceutical composition of claim 1, wherein ketamine is administered parenterally. 2. The pharmaceutical composition of claim 1, wherein ketamine improves weight loss due to cachexia. 2. The pharmaceutical composition of claim 1, wherein ketamine increases the survival rate of the subject. The pharmaceutical composition according to claim 1, wherein the chemotherapeutic agent is fluorouracil (5-FU).